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Glycoproteins - protein + a few sugars - CHO is specific region for ID by other proteins - e.g.

, MHC class I and blood group antigens - also binding sites for Ag (viruses/ parasites) Proteoglycans (sugars with a little protein) - e.g., mucopolysaccharide, glycosaminoglycans - sugars + a few proteins - cell surfaces, ECM, CHO = anionic network - anticoagulation, compression, adhesion, structure Blood Group antigens - O: minimal CHO, ending in fucose - A: glycosyl transferase extends chain by adding Gal-N-Ac - B: glycosyl transferase extends chain by adding Gal Targetting - Mannose-6-P  lysosome - Sialic acid  secretory (or membrane bound if containing v. hydrophobic region) I cell disease - mucolipidosis - acid hydrolases necessary for proper lysosomal function are missing - N-acetyl glucosamine phosphotransferase is deficient o Enzymes lacks M-6-P (no targeting!) Synthesis of N-linked glycoproteins + protein targeting - targeting begins in the ER (cytoplasm proteins don’t have CHO) - dolichol phosphate = carrier of core oligosaccharides to be added - sugar is attached to every amide N of asparagines; must be Asn – XThr or Asn – X – Ser - partially processed in ER where 3 glucose and 1 mannose are removed - then, Golgi, sugars are added or removed Sunthesis of O-linked glycoproteins - Unlike N-linked, sugars are added sequentially instead of all at once! - Added to Ser or Thr Amino Acid Metabolism - 20% daily energy goes to resynthesizing proteins - N is lost from humans as HCO3- and NH4+ - α -KG ALWAYS participates in transamination

another way to transaminate .“ping-pong” reaction o this is why transamination doesn’t deplete CAC of integral intermediates!! st .2 step = “Pong” o enzyme-B6-NH2 + αKG  enzyme-B6 + Glu o enzyme catalyzes the reverse reaction using a different ketoacid Basically. then αKG can be used to make a new AA… never running out of ketoacids… make one. net release of AA into blood o Ala and Glu are > 50% total . lys. use one! Important Reaction: Oxaloacetate + Glutamate  aspartate + α KG b/c aspartate is the amino donor in urea synthesis and adenine synthesis Glucose-Alanine Cycle . you use one amino acid and Vit B6 to make one αKacid. thr Role of pyridoxal phosphate (Vitamin B6) .Excess Ala is formed .- transamination o removes AA’s α amino group as an intermolecular redox reaction o α carbon that receives amino group is at aldehyde or ketone oxidative levels o α carbon that donates amino group is at alcohol level Phenylalanine – NH3 NH3-Glutamate + αKG  Phenylpyruvate + o transamination to α-KG to form glutamate occurs with 17 AAs  AA + αKG  _______ + glutamate  Exceptions are glu.in post-absorptive state (eating).1 step = “Ping” o Phe + enzyme-B6  ketoacid (phenylpyruvate) + enzyme-B6NH2 o AA donates is α amino group to enzyme-bound B6 nd .

tyrosine ** cysteine synthesis requires #2 and # 3.g.. where lactate instead of Ala is exported from muscle Glutamate needs an oxidative deamination catalyzed by glutamic dehydrogenase o Glutamate + NAD  αKG + NADH + NH4 o v. ALT reaction runs in reverse o Get pyruvate for glucose synthesis o Get amino group for urea synthesis o Different from Cori Cycle. Threonine. Matt!) Nonessential Amino Acids .phenylketourics have no phenylalanine hydroxylase o have to avoid excess consumption Phe o tyrosine has to be supplemented Synthesis of Nonessential AAs 1..g. unfavorable o Equilibrium overcome in 2 ways:  Consumption of NH4 by urea synthesis  Can also form αKG by an alternate route = purine nucleotide cycle • GTP hydrolysis makes this rxn favorable! Essential Amino Acids . minor chemical transformations of Kreb’s cycle intermediates a.. e. Tryptophan MT. glutamate 2.tyrosine cannot (is synthesized from phenylalanine) .- - o Branched chain AAs + αKG  ketoacids + Glu o Glu + pyruvate + ALT  alanine + αKG When Ala gets to liver. Isoleucine. serine.nine are essential o Methionine.10 of the 11 can be synthesized by glucose . Leucine. modification of serine. chemical modification of intermediates of glucose metabolism a. Phenylalanine. but sulfur atom is derived from methionine… Cysteine biosynthesis requires SAM . Valine. glycine 3. e. PHILLy VT (thanks. Histidine. chemical transformation of dietary essential AAs a.SAM is also used to methylate carboxylate side chains of Asp – Glu and CG doublets in genome . e.g. Lysine.

malate shuttle (+2ATP)  net ATP loss of 2. The amount of creatinine in the urine = filtration rate .Poll functions o Methylate metabolites (e.g. Gly. HCO3-. NH4+ can be excreted by means other than urea: hippuric acid Synthesis of creatine and creatinine .His.creatinine is synthesized at a constant rate in muscle o not reabsorbed in the glomerular filtration!!  :. the THF.urea synthesis consumes 4 ATP + ¼ in transporting citrulline into mitochondria o but.urea is nontoxic.glutamate provides both NH4 molecules o one directly. homocysteine) o Thymine side chain o Purine biosynthesis Metabolsim of NH4 released from AAs .ketogenic  The 1C THF Pool .Urea synthesis is compartmentalized o Only occurs in liver .- Homocysteine donates its CH3 group but then needs to be remethylated Requires THF 1C pool A 1C moiety is transferred from THF to homocysteine Methylation of homocystrine also requires methylcobalamin o 5-Me-THF + homocysteine  methionine o methylo cobalamin Degradation of AAs . Ser.urea synthesis is also regulated by N-acetylglutamate = allosteric activator of carbomyl phosphate synthase o more arginine  more enzyme activity .the higher the NH4 concentration.. NH4 is though! . the higher the synthesis of urea . the other through aspartate . there is a virtually unlimited supply .25 ATP ** when in urea synthesis failure: if treated w/ large doses of benzoic acid. and formate donate 1C fragments to the pool o Since serine can be derived from glucose.glucogenic  can give rise to a net production of glucose .

Lys-Lys.pre-pro-glucagon ..g.dimerization results in auophosphorylation .HRE = hormone reponse element .. several Met-ENK.integral membrane proteins .e. again. GLP1 o expression depends on specific proteases and + stimuli One gene = inactive precursor of a single hormone . more creatine PO4 Hormones . more muscle mass.Protein Kinase catalytic domains o ATP-binding lobe | substrate binding lobe Catalytic center Activation Loop Polypeptide hormones are synthesized as inactive pre-pro-hormones .g.pro-hormone = after signal sequence is claved off in RER . pre-pro-opiomelanocortin (POMC) – 7 or 8 diff. one Leu-ENK One gene = several different hormones .serine proteases cleave pro-hormone at dibasic AAs o e. more creatine.hormone binding to EC domain  dimerization .e.processing begins in trans-Golgi o continues in secretory vesicles o final step can occur in extracellular fluid after secretion One gene = multiple copies of a single hormone .e.g.- creatinine synthesized in muscle by a first order nonenzymatic cyclization of creatine phosphate o more creatine PO4  more creatinine. insulin o mature = 2 chains connected by sulfide bonds o immature = B chain – C peptide – A chain Receptor Tyrosine Kinases .. and. Lys-Arg.g. or Arg-Arg o cleave on carboxyl side of site .lipophilic hormone and its receptor bind to the HRE (transcriptional activating region ) of a gene .. Hormones .major hormones with opposite effect o glucagons v.

gluconeogenesis . membranes a. b. IRS as a docking site for signaling components a. PTB: phosphotyrosine b. In class II receptors 2.I: monomers in the absence of ligands . A given receptor binds to multiple signaling molecules Intracellular Relays .g. crosslink monomers Intracellular signaling by tyrosine kinase receptors 1. SH2.in liver.2nd messengers generate effector enzymes o activate cytoplasmic protein kinases . insulin stimulates MAPK pathway and targets PHAS-1 .Three classes of tyrosine kinases .III: hormones are dimers themselves.E. Conserved domains are the building blocks of these complexes a. autophosphorylation of cytoplasmic domain and IRS (docking site) . Ras = monomeric G protein + adapter protein o Activates GEF (guanine exchange factor) o Activates Raf = protein kinase  MAPK kinase cascade  Raf has a negative region domain at its N-terminus  Ras binding causes Raf to assume an open conformation • Exposes catalytic domain = ACTIVE  Raf phosphorylates 2 serines in the activation loop of MAPK Or. PH: phospholipids.G protein activation of protein kinase cascade ..PI3 kinase has SH2 domain o Binds to activated receptor o Phosphorylates IP3 at 3rd position o Causes recruitment of PKB from cytosol to membrane *** can use either/or.insulin also changes the phosphorylation/dephosphorylation of enzymes . but usually both are needed to simulataneously activate different relays Insulin Receptor Signal Pathway . SH3: proline rich sequence c. and c for signaling proteins 3.II: ligand binding causes conformational change in receptor dimers.phosphorylation of pHAS-1 activates eIF4e (protein synthesis) o change b/w glycolysis v. .

therefore. insulin binds to the insulin receptor 2.Gs  stimulate adenylate cyclase . remember: IRS-dependent activation of PI3K  translocation of GLUT4 to plasma membrane b. adapter molecule (Grb2 + Ras) a.Gq  stimulates phospholipase Cβ .mice develop Type II diabetes b/c of failure of increased β cell mass during d’vel’pmt G protein Receptors . interference w/ IRS phosphorylation and docking 2. IRS-P serve as docking sites for: PI3K. GTP exchanged for GDP  when active. so. each of PI3K pathway and Grb2 and Ras pathway are needed for activation of glycogen synthase Type II diabetes 1. 3 IC loops . impaired glucose uptake in fat and muscle cells a. tyrosine phosphatase. activated receptor phosphorylates IRS 3. glucose uptake *** TNFα negatively regulates IRS phosphorylation ** IRS2 -/.G12  stimulates ion channels . dec. β. GLUT4 and :.ligand-binding pocket on EC surface composed of helices IV. VI. Gα dissociates from Gβγ subunits G protein families .C-terminal tail contains sites that can be phosphorylated o Desensitization to stimulatory ligand heterotrimeric G proteins = α. function) 1. inhibitors in cells c.receptors are serpentine o 7 transmembrane spanning domains  3 EC loops. decreased tyrosine kinase activity in target cells b.o changes enyzymatic activation sites (and. decreased IRS receptor function  dec. impaired insulin receptor function a.Gi  inhibits adenylate cyclase . *** PI3K  translocation of GLUT4 receptor b. and VII . and γ subunits o α subunit = GTPase  when receptor binds ligand.

glucagons binds to Gs receptor 2. G protein. adenylate cyclase  increased camp  PKA activity 4. or effector enzyme b. G protein. Gα s stimulates adenylate cyclase 3. Reduced expression of receptor. Increase in the activated time of receptor. DAG stimulates PKC 5. decreased adenylate cyclase  maintained negative reg. or effector enzyme c. GTP-Gαs binds to adenylate cyclase (effector enzyme) 2. Adenylate cyclase stimulation causes an increase in camp 3. PKC phosphorylates substrate proteins GαI inhibits adenylate cyclase (Gβγi stimulates PLC. or effector enzyme 2.ribosylates Gαs w/ ADP . Overexpression of receptor. of PKA 3. PKA cannot phosphorylate its cellular substrates Glucagon . Phospholipase Cβ catalyzes the hydrolysis of PIP2 into IP3 and DAG 3. G protein. camp reveses negative regulation on PKA a. Inappropriate activation of receptor. or effector enzyme Cholera toxin (inappropriate activation) . GTP-GαI binds to adenylate cyclase and inhibits it 2. G protein. same as Gαq) 1. IP3  release of Ca++ from the ER 4. Failure of pathway function by hormone resistance a.GTPase is inhibited .Gets trapped in active state!! . G protein. or effector enzyme b. Constitutive Pathway Function by hormone independent response a. PKA phosphorylates specific cellular proteins Gαq stimulates phospholipase Cβ 1. Impaired activation of receptor.Free subunits (Gα or Gβγ) bind to effector enzyme + trigger production of 2 nd messenger Gαs stimulates adenylate cyclase 1.acts almost exclusively on the liver 1. catalytic subunit of PKA controls transcription factor CREB When your G-protein-linked signaling pathway goes WRONG! 1. PKA was under pseudosubstrate inhibition 4. GTP-Gαq binds to phospholipase Cβ (effector enzyme) 2.

cholesterol  mitochondria . progestins i.prevents GαI from inhibiting adenylate cyclase . stimulated by LH 5.Asp578 residue important for H bonding w. 21C  from corpus luteum ii. glucocorticoids i. for cortisol . 18 C  from ovary iii. stimulated by ACTH 3.decreased production of Gαs o target cells are therefore unresponsive Steroid Biosynthesis .increased camp Familial Precocious Puberty (inappropriate activation) .mutation sub’s glu for asp o no H bonding . adjacent helix o Leads receptor to “off” conformation .. 21C  from adrenal cortex ii.ribosylates GαI w/ ADP . 19C  from testis ii. androgens i. estrogens i. stimulated by AII/AIII 4.intermediate  mito .intermediate  ER . stimulated by LH 2.g. mineralocoticoids i.LH receptor is now parially active even w/o ligand/hormone Pseudohypothyroidism (reduced expression) . or ER enzymes convert cholesterol to these steroid hormones e.Five major classes of steroid hormones 1.inhibits the exchange of GDP for GTP . 21C  from adrenal cortex ii.- Elevated levels of camp cause intestinal cells to secrete large volumes of fluid Pertussis toxin (impaired activation) . stimulated by FSH ***Progesterone = intermediate for the formation of all of these hormones *** Mito.

require NADPH and O2 .also requires specialized O2-transport chains Adrenal Hormones Zona glomerulosa = mineralocorticoids Zona fasciculate = glucocorticoids Zona reticularis = androgens/ DHEA .catalyzed by monooxygenases o members of the cytochrome P450 family .- secretion hydroxylation reactions convert cholesterol to steroid hormones .

angiotensin II and III bind to their cell surface receptor .concensus HRE = 2 short repeats = half sites o separated by .DAG and Ca++ activate PKC .ACTH binds cell membrane receptor .This activation increases cAMP (from Gαs) and Ca++ (from Gβγi) .HBD = hormone binding domain at C terminus o Transcriptional activation domain is adjacent o May bind heat shock protein (HSP) when hormone is not bound . and Ca++ .PKC phosphorylates key proteins for aldosterone secretion Steroid Hormone Receptors .increased blood glucose .Male gonadal hormones Leydig cells: testosterone Female gonadal hormones Theca cells: androgens (which will then be converted to estrogens by granulosa) Granulosa cells: estrogens Corpus Luteum: progesterone Cortisol secretion (molecular action) .This binding activates Gs .5 base pairs o can be inverted (homodimers) or direct (heterodimers) Function of Cortisol .stress response .activates Gq . DAG.immune suppression .DBD = DNA binding domain o Centrally located o Cys-X2-Cys = zinc fingers x2  ZF1 = DNA binding  ZF2 = dimerization .Variable domain = N terminus .cAMP activates PKA Renin/Angiotensin (aldosterone secretion) .increased IP3.Each receptor recognizes a specific HRE in the transcriptional control region .mechanism o transcriptional regulation of gene expression .

mechanism o changes flux of ions across target cell membranes o stimulates phospholipase and fatty acid synthesis and acyltransferase .o suppresses immune system by inhibiting NFkB  increases production of negative regulation products  also cortisol binds to NFkB to prevent its action Function of Aldosterone .acts on distal convoluted tubule o Na+ retention o K+ and H+ excretion .

Diminished cortisol and aldosterone (because no 21 α means no pathway to those two!) .CAH = congential adrenal hyperplasia o Masculization of females (male 2nd ary sex characteristics) .Increased androgens (only way to go) .Increase in ACTH production causes the hyperplasia .Disturbances in Adrenal Corticosteroid secretions .21α -hydroxylase and 11β -hydroxylase = 2 most common defects o porter-silber color reaction will distinguish  looks for 11β-hydroxycortisol Cushings Syndrome = ACTH overproduced o Oversecretion of cortisol and androgens .